Atorvastatin Inhibits T Cell Activation through 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase without Decreasing Cholesterol Synthesis
| Autor: | Hanns-Martin Lorenz, Martin Schiller, Freja Busse, Joachim R. Kalden, Birgit Schätz, Norbert Blank, Stefan Krienke, Anthony D. Ho |
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| Rok vydání: | 2007 |
| Předmět: |
T-Lymphocytes
Atorvastatin T cell Immunology Protein Prenylation Antigen-Presenting Cells G(M1) Ganglioside Biology Lymphocyte Activation Jurkat cells Immunological synapse Interferon-gamma Jurkat Cells chemistry.chemical_compound medicine Humans Immunology and Allergy Pyrroles Calcium Signaling IL-2 receptor Phosphorylation Extracellular Signal-Regulated MAP Kinases Cells Cultured Cell Proliferation Cholesterol Cell Membrane T-cell receptor HLA-DR Antigens Growth Inhibitors Cell biology medicine.anatomical_structure chemistry Heptanoic Acids Hydroxymethylglutaryl-CoA-Reductases NADP-dependent Protein prenylation lipids (amino acids peptides and proteins) Biomarkers Immunosuppressive Agents medicine.drug |
| Zdroj: | The Journal of Immunology. 179:3613-3621 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | The localization of the TCR and other signaling molecules in membrane rafts (MR) is essential for the activation of T lymphocytes. MR are stabilized by sphingolipids and cholesterol. Activation of T lymphocytes leads to the confluence of small MR and the formation of an immunological synapse that is essential for sustained activation and proliferation. In this study, we investigated the effect of statins on MR and T cell activation in superantigen-stimulated human PBMC. Atorvastatin significantly inhibited cellular activation and proliferation. The binding of cholera toxin B subunit to isolated MR and to whole cells was inhibited by low doses of statins. Statins reduce the association of critical signaling proteins such as Lck and linker of activation in T cells with MR in stimulated T cells. The expression of activation markers CD69 and CD25 was inhibited. Several statin-mediated mechanisms, such as a lower stimulation with MHC-II, an inhibition of costimulation by direct binding of statins to LFA-1, a reduced secretion of cytokines, or a depletion of cellular cholesterol pools, were excluded. Inhibition of protein prenylation had a similar effect on T cell proliferation, suggesting that a reduced protein prenylation might contribute to the statin-mediated inhibition of T cell activation. Statins induce both lower levels of low-density lipoprotein cholesterol and inhibition of T cell activation, which might contribute to an inhibition of atherosclerosis. |
| Databáze: | OpenAIRE |
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